Gossypol is a polyphenolic triterpene derivative having the chemical formula ##STR3## wherein b and c are tautomers of the aldehyde a. Gossypol exists primarily as the aldehyde form in nonpolar solvents and is represented as such throughout the specification and claims. Gossypol is found in certain types of cotton plants and is the main toxic material found therein. As such, it has limited the use of cottonseed meal as a source of dietary protein for monogastric animals including man. Gossypol, however, exhibits a number of useful biological properties which render it of interest for medical purposes.
Gossypol was studied for its effects on infertility and as a vaginal spermicide in China because of the discovery that the use of cotton-seed oil in cooking induced infertility in men (National Coordinating Groups on Male Fertility, Chinese Med. J. 4(6): 417-428 (1978)). This feature was used to attempt to produce a male contraceptive using gossypol as the active agent (U.S. Pat. No. 4,381,298) as well as a vaginal spermicide (U.S. Pat. No. 4,297,341). Similar properties have been attributed to the compound hemigossypol. (Manmade, et al., Experiencia 39: 1276 (1983).
Gossypol has also been shown to have antiviral properties, being capable of inactivating parainfluenza type 3 and herpes simplex viruses (Dorsett et al., J. Pharm. Sci. 64: 1073 (1975)). Antiparasitic activity has also been found to be associated with gossypol.
Growth of both Trypanosoma cruzi (Montamat et al., Science 218: 288 (1982)) and Plasmodium falcicarum (Heidrich et al., IRCS Med. Sci 11: 304 (1983)) are inhibited by gossypol. Any practical applications of these properties have been prevented though by the toxicity and unpleasant side effects produced by gossypol.
A considerable body of research suggests that the toxicity of this compound may be related to reactions of the aldehyde groups in the molecule. The removal of its aldehyde groups, however, may lead to a reduction in toxicity as well as biological activity. It is thus difficult to predict whether any gossypol molecule without the aldehydes will exhibit activity similar to the natural molecule. It is also substantially unpredictable as to what, if any, substituent groups might be used as appropriate replacements for the aldehyde groups which might mimic the biological activity of the original compound.
U.S. Pat. No. 4,806,568 by the present inventors discloses a series of gossypol derivatives having activities similar to those of the parent compound, although lacking free aldehyde moieties. These compounds were shown to be useful in the treatment of malaria and some viral diseases, such as those caused by herpes simplex virus.
The natural product gossypol and known gossypol derivatives were found to exhibit antiviral activities against herpes simplex virus type II (Radloff, R. J. et al, Pharmacological Res. Comm. 18: 1063-1073 (1986)). This, as well as other reports of antiviral properties of gossypol, suggest that the antiviral activities of gossypol and derivatives result from the effects of these drugs on the viral envelope. This conclusion is based upon the observation that these known drugs do not inhibit the replication of naked viruses. In addition, these known drugs are active against both RNA and DNA enveloped viruses.
Acquired immunodeficiency syndrome (AIDS) is a fatal disease that results from infection by human immunodeficiency virus (HIV) (Gallo, R. C., et al, Science 220: 865-867 (1983)); Barre-Sinoussi, F. et al, Science 220: 868-871 (1983)). At present, the only approved drug for use against HIV infections is 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine) (Fischl, M. A., et al, New Eng. J. Med. 317: 185-191 (1987)). Its hematologic toxicity limits, and in some cases precludes, the use of AZT in many HIV-infected patients (Richman, D. D. et al, New Eng. J. Med. 317, 192-197 (1987)). Moreover, it has been recently reported that the HIV virus may develop resistance to AZT after prolonged exposure (Larder, B. A., et al, Science 243: 1731-1734 (1989)) AZT is an inhibitor of the enzyme reverse transcriptase (RT), a key viral enzyme. It is believed that AZT exerts its effect on HIV by interfering with the RT enzyme.
In view of the AZT toxicity and also the resistance shown by patients to AZT, there is a critical need for new antiviral drugs directed against HIV, particularly for new drugs that do not share the same mechanism as AZT.